1. Technical Field
The present invention generally relates to a novel polymorph of lercanidipine hydrochloride and processes for its preparation. The present invention also generally relates to a process for the preparation of an amorphous form of lercanidipine hydrochloride and a process for the purification of lercanidipine hydrochloride.
2. Description of Related Art
Lercanidipine hydrochloride, also known as 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethylethylmethyl ester hydrochloride, is represented by the structure of Formula I.
Lercanidipine hydrochloride is a synthetic antihypertensive calcium channel blocker sold under the brand names Lercadip, Lerdip, Lerzam, Zanedip, and Zanidip®. Lercanidipine hydrochloride is a dihydropyridine calcium channel blocker used for the treatment of hypertension. It can reduce systemic arterial blood pressure with a long duration of action and is believed to slow the progression of atherosclerosis. See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 973, monograph 5465.
European Patent No. 0153016 (“the '016 patent”) and U.S. Pat. No. 4,968,832 (“the '832 patent”), herein incorporated by reference, disclose lercanidipine hydrochloride. The '016 and '832 patents further disclose processes for the preparation of lercanidipine hydrochloride and the amorphous form of lercanidipine hydrochloride. Drawbacks associated with these processes include, for example, the production of impurities. Accordingly, it would be advantageous to reduce the level of impurities in the preparation of lercanidipine hydrochloride.
U.S. Pat. No. 5,912,351 discloses a simpler process for the preparation of lercanidipine hydrochloride. It involves the reaction of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid with thionyl chloride in dichloromethane and dimethylformamide at a temperature between −4 and +1° C. and subsequent esterification of the obtained acid chloride with 2, N-dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propyl alcohol at a temperature between −10 and 0° C. The process yields lercanidipine hydrochloride in an anhydrous non-hygroscopic crystalline form, and avoids the formation of unwanted by-products and the subsequent purification on chromatography columns.
One impurity believed to be present in the production of lercanidipine hydrochloride is 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 2-[N-(3,3-diphenyl propyl)-N-methylamino]-1,1-dimethyl ethyl propyl diester, as determined from an HPLC analysis of different batches of lercanidipine hydrochloride produced by the reaction of butanoic acid, 2-[(3-nitrophenyl)methylene]-3-oxo-2-[(3,3-diphenyl propyl)methylamino]-1,1-dimethyl ethyl ester hydrochloride and methyl-3-amino crotonate in the presence of triethyl amine and in n-propanol employing the procedure set forth in Example 16 of EP 0153016. The structure of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 2-[N-(3,3-diphenyl propyl)-N-methylamino]-1,1-dimethyl ethyl propyl diester is represented by the structure of Formula II.

The impurity is formed due to the transesterification of lercanidipine hydrochloride at the 5 position with n-propanol in the presence of HCl in n-propanol. Additionally, this impurity is highly difficult to remove from crude lercanidipine hydrochloride.
U.S. Pat. No. 6,852,737 (“the '737 patent”) discloses crystalline Forms I and II and crude Forms A and B of lercanidipine hydrochloride and processes for their preparation. Crude Form A of lercanidipine hydrochloride is described in Example 2 as having a differential scanning calorimetric (DSC) peak of 150-152° C. Crude Form B of lercanidipine hydrochloride is described in Example 3 as having a DSC peak of 131-135° C. The '737 patent additionally discloses that U.S. Pat. No. 5,912,351 (“the '351 patent”) produces a third crude form of lercanidipine hydrochloride, termed crude Form C. Crude Form C is reported to have a DSC peak of 186-192° C. Additionally, the '737 patent discloses that thermogravimetric studies show that crude Form A contains 3-4% residual ethyl acetate, crude Form B contains 0.3-0.7% residual ethyl acetate, and crude Form C contains 0-0.1% residual solvents. Crystalline Forms I and II of lercanidipine hydrochloride are well characterized by XRD analysis in the '737 patent. Example 12 of the '737 patent discloses that crystalline Form I has a melting temperature (T peak) of 198.7° C. and an onset temperature of 179.8° C., and crystalline Form II has a melting temperature (T peak) of 209.3° C. and an onset temperature of 169.0° C.
WO 2006/089787 discloses amorphous lercanidipine hydrochloride having a purity of at least 95% and a method for its preparation. The method includes dissolving crystalline lercanidipine hydrochloride in an organic solvent to provide a solution and isolating amorphous lercanidipine hydrochloride by either (a) adding water to the solution to form a precipitate and collecting the precipitate or (b) evaporating off the organic solvent.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds to the material that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. A new polymorphic form of lercanidipine hydrochloride has now been discovered.
Efforts are also made to prepare pharmaceutical products of a high grade and with a minimum amount of impurities present. The control of impurities requires a study of various options to decide upon the reaction conditions and testing protocols necessary to insure that drugs which are administered to the public are substantially pure. Accordingly, there remains a need for an improved process for preparing lercanidipine hydrochloride that eliminates or substantially reduces the impurities in a convenient and cost efficient manner to provide substantially pure forms of lercanidipine hydrochloride.